GABA receptor: Difference between revisions
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== Structure == | == Structure == | ||
There are two major classes of GABA receptors abundant throughout neuronal cell types, ionotropic and metabotropic (Cryan, 2005). Metabotropic GABAB receptors are a specific division of the GABA receptor (Kerr, 1995). The GABAB receptor functions as a heterodimer of two subunits, GABAB1 and GABAB2. Heterodimerization is accomplished using coiled-coil motifs within the C-termini and interactions between the transmembrane and extracellular domains (Cryan, 2005). Additionally, there are two GABAB1 isoforms that differ at the N-termini where there are two sushi domains (Cryan, 2005). These sushi domains on the GABAB1 subunit is key to the receptor's interaction with other proteins as well as axonal signaling (Cryan, 2005) | There are two major classes of GABA receptors abundant throughout neuronal cell types, ionotropic and metabotropic (Cryan, 2005). Metabotropic GABAB receptors are a specific division of the GABA receptor (Kerr, 1995). The GABAB receptor functions as a heterodimer of two subunits, GABAB1 and GABAB2. Heterodimerization is accomplished using coiled-coil motifs within the C-termini and interactions between the transmembrane and extracellular domains (Cryan, 2005). Additionally, there are two GABAB1 isoforms that differ at the N-termini where there are two sushi domains (Cryan, 2005). These sushi domains on the GABAB1 subunit is key to the receptor's interaction with other proteins as well as axonal signaling (Cryan, 2005). The two GABAB subunits link together as GABAB2 connects to GABAB1 at the endoplasmic reticulum via their intracellular C-terminus to form the heterodimer GABAB receptor (Sigma Aldrich). The GABAB receptor exists in two different forms - in the resting state (i.e. unbound state) and the active state (i.e. bound state)(Geng, 2013). Geng et. al. has found, using the GABAB crystal structures, that both subunits exist in open conformations while at rest (see above). Upon binding with the agonist, the GABAB1 subunit closes(Geng, 2013) (see below). Additionally, it was found that the agonist is bound in the interdomain crevice of the GABAB1 subunit due to an overlap of amino acid residues (Geng, 2013). | ||
== Function == | == Function == | ||
Revision as of 07:12, 13 November 2015
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GABA receptors are proteins utilized for the primary inhibitory neurotransmitter in vertebrate central nervous systems, gamma-aminobutyric acid or GABA (Kerr, 1995). Upon binding with GABA, GABAB receptors utilize a second messenger amplification pathway that ultimately results in the inhibitory signal for neuronal transmission. This pathway for signal transmission differs from GABAA receptors, which are considered ligand-gated ion channels as the binding of GABA results in the opening of ion channels leading to the inhibition of a neuronal signal.
StructureStructure
There are two major classes of GABA receptors abundant throughout neuronal cell types, ionotropic and metabotropic (Cryan, 2005). Metabotropic GABAB receptors are a specific division of the GABA receptor (Kerr, 1995). The GABAB receptor functions as a heterodimer of two subunits, GABAB1 and GABAB2. Heterodimerization is accomplished using coiled-coil motifs within the C-termini and interactions between the transmembrane and extracellular domains (Cryan, 2005). Additionally, there are two GABAB1 isoforms that differ at the N-termini where there are two sushi domains (Cryan, 2005). These sushi domains on the GABAB1 subunit is key to the receptor's interaction with other proteins as well as axonal signaling (Cryan, 2005). The two GABAB subunits link together as GABAB2 connects to GABAB1 at the endoplasmic reticulum via their intracellular C-terminus to form the heterodimer GABAB receptor (Sigma Aldrich). The GABAB receptor exists in two different forms - in the resting state (i.e. unbound state) and the active state (i.e. bound state)(Geng, 2013). Geng et. al. has found, using the GABAB crystal structures, that both subunits exist in open conformations while at rest (see above). Upon binding with the agonist, the GABAB1 subunit closes(Geng, 2013) (see below). Additionally, it was found that the agonist is bound in the interdomain crevice of the GABAB1 subunit due to an overlap of amino acid residues (Geng, 2013).
FunctionFunction
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It has been found that GABAB receptors provide an inhibitory function through the coupling to G-proteins and the recruitment of second messengers (Bettler, 2004). Presynaptic GABAB receptors effectively repress the influx of calcium ions (Ca2+) via the inhibition of voltage gated Ca2+ channels through the activation of Gβγ subunits (Bettler, 2004). Postsynaptic GABAB receptors then activate the opening of potassium ion (K+) channels, again through the activation of Gβγ subunits (Bettler, 2004). The efflux of potassium ions results in the hyperpolarization of the neuronal membrane due to the greatly negative Nernst value of potassium in cerebrospinal fluid. This hyperpolarization of the neuronal membrane causes the neuron’s membrane potential to move away from threshold, thus inhibiting the gaba neuronal function (Bettler, 2004). This functions in opposition of the GABAA receptor to control and slow the inhibitory postsynaptic potentials (Cryan, 2005). Aside from the interaction with ion channels, GABAB receptors also inhibit adenylyl cyclase through the Giα/Goα subunits and activate adenylyl cyclase through Gβγ subunits (Bettler, 2004). It has been found that the Giα/Goα subunits inhibit adenylyl cyclase types I, III, V, and VI (Bettler, 2004). Additionally, the Gβγ subunits stimulates adenylyl cyclase types II, IV, and VII (Bettler, 2004). This control of adenylyl cyclase is expected to control neuronal function for a longer period of time compared to the control via ion channels (Geng, 2013). The GABAB1 sushi domains are axonal trafficking signals that help to localize the receptors to glutmatergic terminals (Cryan 2005).
DiseaseDisease
GABAB receptors are targeted for a number of treatments in the clinical setting of neurodegenerative and pathophysiolocial disorders including epilepsy, spasticity, chronic pain, anxiety, depression, schizophrenia, cognitive function, gastro-esophageal reflux and drug dependence and addition (Kerr 2005).
There is increasing evidence that links schizophrenia directly to GABAB receptor deficits. GABBR1, the gene associated with the GABAB1 receptor was found to have a high number of differentially methylated CpGs, or hyper methylation in receptors tested for patients with schizophrenia (Citrine et al. 2009). The receptor 1 gene is on chromosome 6 where the locus is susceptible for multiple sclerosis, epilepsy, and schizophrenia (Sigma Aldrich). Presynaptic dopaminergic terminals have GABAB receptors that are involved in the release of dopamine along with modulation of glutaminergic regulation of dopamine (Citrome et al. 2009).
A possible therapeutic approach utilizing GABAB receptors would be for the treatment substance use disorder (drug addition). Since the GABAB receptor plays a crucial role in mediating behavioral and molecular effects of drug abuse, the GABAB receptor can be utilized as a potential anti-addictive therapeutic strategy (Flip et. al, 2015). Agonists at GABAB receptors can promote abstinence or decrease and control the reinforcing effects of drugs on the mind (Kerr 2005).
ReferencesReferences
Bettler, B., Kaupmann, K., Mosbacher, J., & Gassmann, M. (2004). Molecular structure and physiological functions of GABAB receptors. Physiological reviews, 84(3), 835-867. Cryan, J.F., Kaupman, K. (2005). Don’t worry ‘B’ happy!: a role for GABAB receptors in anxiety and depression. Trends in Pharmacological Sciences, 26(1), 36-43. Geng, Y., Bush, M., Mosyak, L., Wang, F., & Fan, Q. R. (2013). Structural mechanism of ligand activation in human GABAB receptor. Nature, 504(7479), 254-259. Kerr, D. I. B., and J. Ong. "Gaba B receptors." Pharmacology & therapeutics. 67.2 (1995): 187-246. Lloyd, K. G., Bossi, L., Morselli, P. L., Munari, C., Rougier, M., & Loiseau, H. (1985). Alterations of GABA-mediated synaptic transmission in human epilepsy.Advances in neurology, 44, 1033-1044.